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Atsushi Fukai, Satoru Kamekura,
Daichi Chikazu,
Takumi Nakagawa,
Makoto Hirata,
Taku Saito,
Yoko Hosaka,
Toshiyuki Ikeda,
Kozo Nakamura,
Ung-il Chung,
Hiroshi Kawaguchi
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ABSTRACT: To investigate the chondroprotective effect of cyclooxygenase 2 (COX-2) inhibition in experimental osteoarthritis (OA).
The expression of prostaglandin E2 synthetic enzymes was examined by immunostaining of tibial cartilage from mice with surgically induced knee joint instability and from OA patients undergoing total knee arthroplasty. The effect of orally administered celecoxib (10 mg/kg/day and 30 mg/kg/day) or vehicle alone in mice was examined 12 weeks after the induction of OA. To investigate the involvement of COX-1 and COX-2 in OA development, we also created the model in COX-1-homozygous-knockout (Ptgs1-/-) mice and COX-2-homozygous-knockout (Ptgs2-/-) mice. OA severity was assessed using a grading system developed by our group and by the Osteoarthritis Research Society International scoring system.
In mouse and human OA cartilage, the expression of the inducible enzymes COX-2 and microsomal prostaglandin E synthase 1 (mPGES-1) was enhanced, while that of the constitutive enzymes COX-1, cytosolic PGES, and mPGES-2 was suppressed. Daily celecoxib treatment did not prevent cartilage degradation or osteophyte formation during OA development in the mouse model. Furthermore, neither Ptgs1-/- mice nor Ptgs2-/- mice exhibited any significant difference in OA development as compared to wild-type littermates.
The two COX enzymes differ in terms of regulation of their expression during OA development. Nevertheless, experiments using inhibitor and genetic deficiency demonstrated a lack of chondroprotective effect of COX-2 inhibition in the mouse surgical OA model.
Arthritis & Rheumatism 09/2011; 64(1):198-203. · 7.87 Impact Factor
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Akiro Higashikawa,
Taku Saito,
Toshiyuki Ikeda, Satoru Kamekura,
Naohiro Kawamura,
Akinori Kan,
Yasushi Oshima,
Shinsuke Ohba,
Naoshi Ogata,
Katsushi Takeshita,
Kozo Nakamura,
Ung-il Chung,
Hiroshi Kawaguchi
[show abstract]
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ABSTRACT: Type X collagen and runt-related transcription factor 2 (RUNX-2) are known to be important for chondrocyte hypertrophy during skeletal growth and repair and development of osteoarthritis (OA) in mice. Aiming at clinical application, this study was undertaken to investigate transcriptional regulation of human type X collagen by RUNX-2 in human cells.
Localization of type X collagen and RUNX-2 was determined by immunohistochemistry, and their functional interaction was examined in cultured mouse chondrogenic ATDC-5 cells. Promoter activity of the human type X collagen gene (COL10A1) was examined in human HeLa, HuH7, and OUMS27 cells transfected with a luciferase gene containing a 4.5-kb promoter and fragments. Binding to RUNX-2 was examined by electrophoretic mobility shift assay and chromatin immunoprecipitation.
RUNX-2 and type X collagen were co-localized in mouse limb cartilage and bone fracture callus. Gain and loss of function of RUNX-2 revealed that RUNX-2 is essential for type X collagen expression and terminal differentiation of chondrocytes. Human COL10A1 promoter activity was enhanced by RUNX-2 alone and more potently by RUNX-2 in combination with the coactivator core-binding factor beta in all 3 human cell lines examined. Deletion, mutagenesis, and tandem repeat analyses identified the core responsive element as the region between -89 and -60 bp (termed the hypertrophy box [HY box]), which showed specific binding to RUNX-2. Other putative RUNX-2 binding motifs in the human COL10A1 promoter did not respond to RUNX-2 in human cells.
Our findings indicate that the HY box is the core element responsive to RUNX-2 in human COL10A1 promoter. Studies on molecular networks related to RUNX-2 and the HY box will lead to treatments of skeletal growth retardation, bone fracture, and OA.
Arthritis & Rheumatism 01/2009; 60(1):166-78. · 7.87 Impact Factor
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Yosuke Kawasaki,
Fumitaka Kugimiya,
Hirotaka Chikuda, Satoru Kamekura,
Toshiyuki Ikeda,
Naohiro Kawamura,
Taku Saito,
Yusuke Shinoda,
Akiro Higashikawa,
Fumiko Yano,
Toru Ogasawara,
Naoshi Ogata,
Kazuto Hoshi,
Franz Hofmann,
James R Woodgett,
Kozo Nakamura,
Ung-Il Chung,
Hiroshi Kawaguchi
Journal of Clinical Investigation 09/2008; 118(8):2986. · 15.39 Impact Factor
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Yosuke Kawasaki,
Fumitaka Kugimiya,
Hirotaka Chikuda, Satoru Kamekura,
Toshiyuki Ikeda,
Naohiro Kawamura,
Taku Saito,
Yusuke Shinoda,
Akiro Higashikawa,
Fumiko Yano,
Toru Ogasawara,
Naoshi Ogata,
Kazuto Hoshi,
Franz Hofmann,
James R Woodgett,
Kozo Nakamura,
Ung-il Chung,
Hiroshi Kawaguchi
[show abstract]
[hide abstract]
ABSTRACT: cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase-3beta (GSK-3beta; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3beta was associated with enhanced hypertrophic differentiation. Furthermore, cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3beta. Analyses of mice with compound deficiencies in both protein kinases (Prkg2(-/-)Gsk3b(+/-)) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. We found that beta-catenin levels decreased in Prkg2(-/-) mice, while overexpression of cGKII increased the accumulation and transactivation function of beta-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3beta. These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.
Journal of Clinical Investigation 08/2008; 118(7):2506-15. · 15.39 Impact Factor
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Kiyofumi Yamakawa, Satoru Kamekura,
Naohiro Kawamura,
Masatomo Saegusa,
Daisuke Kamei,
Makoto Murakami,
Ichiro Kudo,
Satoshi Uematsu,
Shizuo Akira,
Ung-il Chung,
Kozo Nakamura,
Hiroshi Kawaguchi
[show abstract]
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ABSTRACT: Prostaglandin E synthase (PGES) functions as the terminal enzyme in the biosynthesis of prostaglandin E(2) (PGE(2)) and is a potent regulator of bone and cartilage metabolism. Among the 3 isozymes of PGES, microsomal PGES-1 (mPGES-1) is known to play the most critical role in the production of PGE(2) in pathophysiologic events. This study investigated the roles of mPGES-1 under normal physiologic and pathophysiologic conditions in the skeletons of mPGES-1-deficient (mPGES-1(-/-)) mice.
Skeletons of mPGES-1(-/-) mice and their wild-type littermates were compared by radiologic and histologic analyses. Four models of skeletal disorders were created: bone loss induced by ovariectomy, bone loss induced by hind limb unloading, osteoarthritis (OA) induced by instability in the knee joint, and bone fracture by osteotomy at the tibial midshaft. Expression of the PGES enzymes was examined by immunohistochemistry and real-time reverse transcription-polymerase chain reaction. The cellular mechanism of fracture healing was examined in ex vivo cultures of costal cartilage chondrocytes.
Microsomal PGES-1(-/-) mice had unaffected skeletal phenotypes under normal physiologic conditions. In the bone fracture model, fracture healing was impaired by the mPGES-1 deficiency, with half of the mice remaining in a non-bone union state even after 21 days; normal fracture healing was restored by adenoviral reintroduction of mPGES-1. The other skeletal disorders were not affected by the mPGES-1 deficiency. In vivo and ex vivo analyses revealed an impaired proliferation of chondrocytes in cartilage with the mPGES-1 deficiency, at an early stage of fracture healing.
In these mouse models of skeletal disorders, mPGES-1 was indispensable for bone repair through chondrocyte proliferation, but was not essential for the skeleton under normal physiologic conditions, nor did it play a role in the pathophysiologic conditions of bone loss due to ovariectomy, bone loss due to unloading, or stress-induced OA.
Arthritis & Rheumatism 02/2008; 58(1):172-83. · 7.87 Impact Factor
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Naoto Kosaki,
Hironari Takaishi, Satoru Kamekura,
Tokuhiro Kimura,
Yasunori Okada,
Li Minqi,
Norio Amizuka,
Ung-Il Chung,
Kozo Nakamura,
Hiroshi Kawaguchi,
Yoshiaki Toyama,
Jeanine D'Armiento
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ABSTRACT: Vascular and cellular invasion into the cartilage is a critical step in the fracture healing. Matrix metalloproteinase-13 (MMP-13) is a member of the zinc-dependent endopeptidase family and plays an important role in remodeling of extracellular matrix. Therefore we investigated the possible involvement of MMP-13 in a murine model of stabilized bone fracture healing. Repair of the fracture in MMP-13 deficient (MMP-13(-/-)) mice was significantly delayed and characterized by a retarded cartilage resorption in the fracture callus. Immunohistochemistry indicated severe defects in vascular penetration and chondroclast recruitment to the fracture callus in MMP-13(-/-) mice. Consistent with the observations, the chondrocyte pellets cultured from the MMP13(-/-) mice exhibited diminished angiogenic activities when the pellets were co-cultured with endothelial cells. These results suggest that MMP-13 is crucial to the process of angiogenesis during healing of fracture, especially in the cartilage resorption process.
Biochemical and Biophysical Research Communications 04/2007; 354(4):846-51. · 2.48 Impact Factor
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Satoru Kamekura,
Yosuke Kawasaki,
Kazuto Hoshi,
Takashi Shimoaka,
Hirotaka Chikuda,
Zenjiro Maruyama,
Toshihisa Komori,
Shingo Sato,
Shu Takeda,
Gerard Karsenty,
Kozo Nakamura,
Ung-il Chung,
Hiroshi Kawaguchi
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ABSTRACT: By producing instability in mouse knee joints, we attempted to determine the involvement of runt-related transcription factor 2 (RUNX-2), which is required for chondrocyte hypertrophy, in the development of osteoarthritis (OA).
An experimental mouse OA model was created by surgical transection of the medial collateral ligament and resection of the medial meniscus of the knee joints of heterozygous RUNX-2-deficient (Runx2+/-) mice and wild-type littermates. Cartilage destruction and osteophyte formation in the medial tibial cartilage were compared by histologic and radiographic analyses. Localization of type X collagen and matrix metalloproteinase 13 (MMP-13) was examined by immunohistochemistry. Localization of RUNX-2 was determined by X-Gal staining in heterozygous RUNX-2-deficient mice with the lacZ gene insertion at the Runx2-deletion site (Runx2+/lacZ). Messenger RNA levels of type X collagen, MMP-13, and RUNX-2 were examined by real-time reverse transcriptase-polymerase chain reaction analysis.
RUNX-2 was induced in the articular cartilage of wild-type mice at the early stage of OA, almost simultaneously with type X collagen but earlier than MMP-13. Runx2+/- and Runx2+/lacZ mice showed normal skeletal development and articular cartilage; however, after induction of knee joint instability, they exhibited decreased cartilage destruction and osteophyte formation, along with reduced type X collagen and MMP-13 expression, as compared with wild-type mice.
RUNX-2 contributes to the pathogenesis of OA through chondrocyte hypertrophy and matrix breakdown after the induction of joint instability.
Arthritis & Rheumatism 09/2006; 54(8):2462-70. · 7.87 Impact Factor
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Takashi Yamada,
Hirotaka Kawano,
Yu Koshizuka,
Toru Fukuda,
Kimihiro Yoshimura, Satoru Kamekura,
Taku Saito,
Toshiyuki Ikeda,
Yosuke Kawasaki,
Yoshiaki Azuma,
Shiro Ikegawa,
Kazuto Hoshi,
Ung-il Chung,
Kozo Nakamura,
Shigeaki Kato,
Hiroshi Kawaguchi
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ABSTRACT: Endochondral ossification is an essential process not only for physiological skeletal development and growth, but also for pathological disorders. We recently identified a novel cartilage-specific molecule, carminerin (also known as cystatin 10 and encoded by Cst10), which is upregulated in synchrony with cartilage maturation and stimulates the later differentiation of cultured chondrocytes. Although carminerin-deficient (Cst10-/-) mice developed and grew normally, they had a microscopic decrease in the calcification of hypertrophic chondrocytes at the growth plate. When we created experimental models of pathological endochondral ossification, we observed suppression of chondrocyte calcification during formation of osteoarthritic osteophytes, age-related ectopic ossification and healing of bone fractures in Cst10-/- mice. Cultured Cst10-/- chondrocytes showed a reduction in calcification with activation of an SRY site in the promoter of the gene encoding nucleotide pyrophosphatase phosphodiesterase 1 (NPP1, encoded by Enpp1). Functional NPP1 is required for carminerin deficiency to suppress the pathological endochondral ossifications listed above. Carminerin is the first cartilage-specific protein that contributes to chondrocyte calcification during endochondral ossification under physiological and pathological conditions through the transcriptional inhibition of NPP1.
Nature Medicine 07/2006; 12(6):665-70. · 22.46 Impact Factor
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Fumitaka Kugimiya,
Hiroshi Kawaguchi, Satoru Kamekura,
Hirotaka Chikuda,
Shinsuke Ohba,
Fumiko Yano,
Naoshi Ogata,
Takenobu Katagiri,
Yoshifumi Harada,
Yoshiaki Azuma,
Kozo Nakamura,
Ung-il Chung
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ABSTRACT: Although accumulated evidence has shown the bone anabolic effects of bone morphogenetic proteins (BMPs) that were exogenously applied in vitro and in vivo, the roles of endogenous BMPs during bone formation remain to be clarified. This study initially investigated expression patterns of BMPs in the mouse long bone and found that BMP2 and BMP6 were the main subtypes expressed in hypertrophic chondrocytes that induce endochondral bone formation. We then examined the involvement of the combination of these BMPs in bone formation in vivo by generating the compound-deficient mice (Bmp2+/-;Bmp6-/-). Under physiological conditions, these mice exhibited moderate growth retardation compared with the wild-type (WT) littermates during the observation period up to 52 weeks of age. Both the fetal and adult compound-deficient mice showed a reduction in the trabecular bone volume with suppressed bone formation, but normal bone resorption, whereas the single deficient mice (Bmp2+/- or Bmp6-/-) did not. When a fracture was created at the femoral midshaft and the bone healing was analyzed, the endochondral bone formation, but not intramembranous bone formation, was impaired by the compound deficiency. In the cultures of bone marrow cells, however, there was no difference in osteogenic differentiation between WT and compound-deficient cells in the presence or absence of the exogenous BMP2. We thus concluded that endogenous BMP2 and BMP6 cooperatively play pivotal roles in bone formation under both physiological and pathological conditions.
Journal of Biological Chemistry 11/2005; 280(42):35704-12. · 4.77 Impact Factor
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Masayuki Yamaguchi,
Naoshi Ogata,
Yusuke Shinoda,
Toru Akune, Satoru Kamekura,
Yasuo Terauchi,
Takashi Kadowaki,
Kazuto Hoshi,
Ung-Il Chung,
Kozo Nakamura,
Hiroshi Kawaguchi
[show abstract]
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ABSTRACT: Bone anabolic action of PTH has been suggested to be mediated by induction of IGF-I in osteoblasts; however, little is known about the molecular mechanism by which IGF-I leads to bone formation under the PTH stimulation. This study initially confirmed in mouse osteoblast cultures that PTH treatment increased IGF-I mRNA and protein levels and alkaline phosphatase activity, which were accompanied by phosphorylations of IGF-I receptor, insulin receptor substrate (IRS)-1 and IRS-2, essential adaptor molecules for the IGF-I signaling. To learn the involvement of IRS-1 and IRS-2 in the bone anabolic action of PTH in vivo, IRS-1-/- and IRS-2-/- mice and their respective wild-type littermates were given daily injections of PTH (80 mug/kg) or vehicle for 4 wk. In the wild-type mice, the PTH injection increased bone mineral densities of the femur, tibia, and vertebrae by 10-20% without altering the serum IGF-I level. These stimulations were similarly seen in IRS-2-/- mice; however, they were markedly suppressed in IRS-1-/- mice. Although the PTH anabolic effects were stronger on trabecular bones than on cortical bones, the stimulations on both bones were blocked in IRS-1-/- mice but not in IRS-2-/- mice. Histomorphometric and biochemical analyses showed an increased bone turnover by PTH, which was also blunted by the IRS-1 deficiency, though not by the IRS-2 deficiency. These results indicate that the PTH bone anabolic action is mediated by the activation of IRS-1, but not IRS-2, as a downstream signaling of IGF-I that acts locally as an autocrine/paracrine factor.
Endocrinology 07/2005; 146(6):2620-8. · 4.46 Impact Factor
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Journal of Bone and Mineral Metabolism 02/2005; 23(5):337-40. · 2.27 Impact Factor
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Journal of Bone and Mineral Metabolism 02/2005; 23(3):200-4. · 2.27 Impact Factor
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[show abstract]
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ABSTRACT: During vertebrate skeletal development, the appendicular skeleton forms through endochondral ossification, which involves the intricately regulated multistep differentiation of mesenchymal cells. During this process, mesenchymal condensations initially differentiate into chondrocytes. Then chondrocytes in the center further differentiate into hypertrophic chondrocytes. Hypertrophic chondrocytes express a number of osteogenic factors and induce bone formation. Although numerous studies have provided novel insights into the regulation and function of cartilage development, little is known about the intracellular signaling pathways regulating chondrocyte hypertrophy. Recent study revealed that cyclic guanosine monophosphate (cGMP)-dependent protein kinase II (cGKII) coupled the stop of proliferation and the start of hypertrophic differentiation of chondrocytes. Herein, we review the molecular mechanism of regulation of chondrocyte hypertrophy by cGKII and the interaction between cGKII and other signaling pathways.
Modern Rheumatology 02/2005; 15(6):391-6. · 1.58 Impact Factor
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ABSTRACT: To regenerate permanent cartilage, it is crucial to know not only the necessary conditions for chondrogenesis, but also the sufficient conditions. The objective of this study was to determine the signal sufficient for chondrogenesis.
Embryonic stem cells that had been engineered to fluoresce upon chondrocyte differentiation were treated with combinations of factors necessary for chondrogenesis, and chondrocyte differentiation was detected as fluorescence. We screened for the combination that could induce fluorescence within 3 days. Then, primary mesenchymal stem cells, nonchondrogenic immortalized cell lines, and primary dermal fibroblasts were treated with the combination, and the induction of chondrocyte differentiation was assessed by detecting the expression of the cartilage marker genes and the accumulation of proteoglycan-rich matrix. The effects of monolayer, spheroid, and 3-dimensional culture systems on induction by combinations of transcription factors were compared. The effects of the combination on hypertrophic and osteoblastic differentiation were evaluated by detecting the expression of the characteristic marker genes.
No single factor induced fluorescence. Among various combinations examined, only the SOX5, SOX6, and SOX9 combination (the SOX trio) induced fluorescence within 3 days. The SOX trio successfully induced chondrocyte differentiation in all cell types tested, including nonchondrogenic types, and the induction occurred regardless of the culture system used. Contrary to the conventional chondrogenic techniques, the SOX trio suppressed hypertrophic and osteogenic differentiation at the same time.
These data strongly suggest that the SOX trio provides signals sufficient for the induction of permanent cartilage.
Arthritis & Rheumatism 12/2004; 50(11):3561-73. · 7.87 Impact Factor
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Hirotaka Chikuda,
Fumitaka Kugimiya,
Kazuto Hoshi,
Toshiyuki Ikeda,
Toru Ogasawara,
Takashi Shimoaka,
Hirotaka Kawano, Satoru Kamekura,
Atsuko Tsuchida,
Norihide Yokoi,
Kozo Nakamura,
Kajuro Komeda,
Ung-Il Chung,
Hiroshi Kawaguchi
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ABSTRACT: The Komeda miniature rat Ishikawa (KMI) is a naturally occurring mutant caused by an autosomal recessive mutation mri, which exhibits longitudinal growth retardation. Here we identified the mri mutation as a deletion in the rat gene encoding cGMP-dependent protein kinase type II (cGKII). KMIs showed an expanded growth plate and impaired bone healing with abnormal accumulation of postmitotic but nonhypertrophic chondrocytes. Ex vivo culture of KMI chondrocytes reproduced the differentiation impairment, which was restored by introducing the adenovirus-mediated cGKII gene. The expression of Sox9, an inhibitory regulator of hypertrophic differentiation, persisted in the nuclei of postmitotic chondrocytes of the KMI growth plate. Transfection experiments in culture systems revealed that cGKII attenuated the Sox9 functions to induce the chondrogenic differentiation and to inhibit the hypertrophic differentiation of chondrocytes. This attenuation of Sox9 was due to the cGKII inhibition of nuclear entry of Sox9. The impaired differentiation of cultured KMI chondrocytes was restored by the silencing of Sox9 through RNA interference. Hence, the present study for the first time shed light on a novel role of cGKII as a molecular switch, coupling the cessation of proliferation and the start of hypertrophic differentiation of chondrocytes through attenuation of Sox9 function.
Genes & Development 11/2004; 18(19):2418-29. · 11.66 Impact Factor
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Takashi Shimoaka, Satoru Kamekura,
Hirotaka Chikuda,
Kazuto Hoshi,
Ung-Il Chung,
Toru Akune,
Zenjiro Maruyama,
Toshihisa Komori,
Michihiro Matsumoto,
Wataru Ogawa,
Yasuo Terauchi,
Takashi Kadowaki,
Kozo Nakamura,
Hiroshi Kawaguchi
[show abstract]
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ABSTRACT: Insulin receptor substrate-1 (IRS-1) is an essential molecule for intracellular signaling of insulin-like growth factor (IGF)-I and insulin, both of which are potent anabolic regulators of bone and cartilage metabolism. To investigate the role of IRS-1 in bone regeneration, fracture was introduced in the tibia, and its healing was compared between wild-type (WT) mice and mice lacking the IRS-1 gene (IRS-1(-/-) mice). Among 15 IRS-1(-/-) mice, 12 remained in a non-union state even at 10 weeks after the operation, whereas all 15 WT mice showed a rigid bone union at 3 weeks. This impairment was because of the suppression of callus formation with a decrease in chondrocyte proliferation and increases in hypertrophic differentiation and apoptosis. Reintroduction of IRS-1 to the IRS-1(-/-) fractured site using an adenovirus vector significantly restored the callus formation. In the culture of chondrocytes isolated from the mouse growth plate, IRS-1(-/-) chondrocytes showed less mitogenic ability and Akt phosphorylation than WT chondrocytes. An Akt inhibitor decreased the IGF-I-stimulated DNA synthesis of chondrocytes more potently in the WT culture than in the IRS-1(-/-) culture. We therefore conclude that IRS-1 deficiency impairs bone healing at least partly by inhibiting chondrocyte proliferation through the phosphatidylinositol 3-kinase/Akt pathway, and we propose that IRS-1 can be a target molecule for bone regenerative medicine.
Journal of Biological Chemistry 05/2004; 279(15):15314-22. · 4.77 Impact Factor
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Toru Akune,
Shinsuke Ohba, Satoru Kamekura,
Masayuki Yamaguchi,
Ung-Il Chung,
Naoto Kubota,
Yasuo Terauchi,
Yoshifumi Harada,
Yoshiaki Azuma,
Kozo Nakamura,
Takashi Kadowaki,
Hiroshi Kawaguchi
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ABSTRACT: Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARgamma, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARgamma-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARgamma gene. Heterozygous PPARgamma-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARgamma haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARgamma haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARgamma-dependent regulation of bone metabolism in vivo, in that PPARgamma insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.
Journal of Clinical Investigation 04/2004; 113(6):846-55. · 15.39 Impact Factor
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Yosuke Kawasaki,
Fumitaka Kugimiya,
Hirotaka Chikuda, Satoru Kamekura,
Toshiyuki Ikeda,
Naohiro Kawamura,
Taku Saito,
Yusuke Shinoda,
Akiro Higashikawa,
Fumiko Yano,
Toru Ogasawara,
Naoshi Ogata,
Kazuto Hoshi,
Franz Hofmann,
James R Woodgett,
Kozo Nakamura,
Ung-Il Chung,
Hiroshi Kawaguchi
